Polyethylene glycol suppository bases



2,975,099 POLYETHYLENE GLYCOL SUPPOSITORY BASES Jere E. Goyan, Ann Arbor, and Milton Wruble, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Micln, a corporation of Michigan No Drawing. Filed June 25, 1958, Ser. No. 744,345

6 Claims. (Cl. 167-64) This invention relates to an improved base for shaped pharmaceutical preparations and more particularly to a base which possesses chemical and physical properties United States a tent There are certain disadvantages associated with the aforementioned bases. Cacao butter lacks storage-stability under warm conditions and often becomes rancid. Uncontrolled absorption of the medicament accompanying the cacao butter is not unlikely. Glycerin and gelatin during storage. The high molecular weight polyethylene gylcols lack lubricity and often produce quite brittle shaped preparations. The soap-based shaped preparations have an extremely limited field of usefulness. Handrolling of shaped preparations is a costly, small 'unit operation not adaptable to large scale manufacturing. Pour-molding requires elevated temperatures to ensure the easy flow of the ingredients into the mold and is thus unsatisfactory for shaped preparations containing active ingredients susceptible to elevated temperatures. Although pressure-molding is widely used and is often satisfactory, nevertheless, such a method leaves rriuch to be desired in the way of economy and ease of large-scale production. The method of extrusion-molding offers the reduced costs and the increased production which have been long-sought in the field of shaped pharmaceutical preparations. However, the effect of the heat produced during the extrusion step, the necessity for the presence of lubricating properties without compromising firmness, and the amount and combination of inert solid adjuvants critical to water-dispersibility and to extrudability have presented unsolved problems in the field of extrusionmolding of shaped pharmaceutical preparations. These problems have resisted solution by methods and formulations known in the art until the instant invention.

It is an object, therefore, of the instant invention to provide a base for shaped pharmaceutical preparations which is free from the prior art problems encountered in extrusion-molding. Another object is to provide such a base which is water-dispers-ible. An additional object is to provide a storage-stable base for shaped pharmaceutical preparations. Yet'another object is to provide such a base which is compatible with awide variety of active medicaments. Additional objects will be apparent to those skilled in the art to which this invention pertains.

The foregoing and additional objects have been accom- .35 bases tend to lose moisture and become less soluble plished by the provision of a pharmaceutical base suitable for shaping by extrusion and comprising a solid poly ethylene glycol of molecular weight from about 4000 to about 6000; a liquid polyethylene gylcol soluble in said solid polyethylene glycol; a non-toxic, nonionic solid oil,- soluble surfactant; spermaceti, a non-toxic, nonionic solid water-soluble surfactant; and a non-toxic, solid 'adjuvant mixture of which between about eighty percent and about ninety percent by Weight is water-soluble. The physical properties of the various individual ingredients, by interaction, contribute to the properties of the formulated composition the characteristics which guarantee extrudability, water-'dispersibility and storage-stability.

The amounts and proportions of the various ingredients of the base will naturally vary with the amounts of the medicinal ingredients incorporated therein. However, it has been found that the following ranges of the base ingredients are satisfactory for most purposes Ingredient Percent of Base by- V Weight Solid polyethylene glycol about 23 to about. 35,. Liquid polyethylene glycol i about, 10 to about 13. Solid oil-soluble surfactant about 9 to about 11.-

about 10 to about 12. about 4 to about 6.

about 26 to about; 40.

Sperrnac ti Solid water-soluble surfactant Solid adjuvant The preferred solid polyethylene glycol has a molecular weight of about 6000; however, the molecular weight can vary from about 4000 to about 6000. Said glycols are referred to as PEG. 4000 and PEG. 6000. The preferred liquid polyethylene glycol has a molecular weight of about 400; however, the molecular weight can vary from about 200 to about 600. Said glycols are referred to as P.E.G. 200, P.E.G. 400 and BBQ 600. The preferred oil-soluble surfactant is polyoxyethylene sorbitan monostearate (Tween 61); however, polyoxyethylene sorbitan tristearate (Tween 65) can be used. The pre ferred water-soluble surfactant is an ethylene oxide-polyproplyene gylcol condensation product of the formula.

' soluble component can vary from about eighty percent to about ninety percent by weight. Beta lactose is preferred as the water-soluble adjuvant. However, sucrose,

dextrose, sodium chloride and sodium sulfate, for example, can be substituted in whole or in part therefor.

The balance of the adjuvant ispreferably corn starch,

However, the starch can be mixed with small amounts of methylcellulose, guar gum, or purified wood cellulose.

The amounts and proportions of the medicament or medicaments to be incorporated into the base will natua rally vary with the specific medicament and the treatment required, for example, local or systemic treatment. For most purposes from about 0.5 percent to about five percent by weight of the final shaped composition is satisfactory; however, up to about twelve percent by weight of the medicament can be used.

The general method for preparation of the base involves the utilization of heat to form a warm mixture of the higher-melting point ingredients'. To this warm mixture is added a dispersion of the medicinal ingredients, as desired, and the inert solid adjuvants in the liquid propylene glycol, and the'whole" is r'n'ixe'dun'til unifo'rrfii The composition can be refrigerated prior to extrusionmolding without imparting any extrusion-molding resistant properties thereto.

Various medicinal ingredients can be incorporated into the base composition. The said ingredients and mixtures thereof depend on the required type of the finished composition; for example, preparations for nasal, urethral, vaginal and rectal insertion; and the type of medication required, for example, local and systemic medication.

ary amyltricresols; anaesthetics, for example, benzocaine, procaine, tetracaine; vasoconstrictors, for example, epinephrine, phenylephrine and their therapeutically active salts; analgesics, for example, caffeine and ergotamine tartrate, acetylsalicylic acid, acetophenetidin, N-acetyl-paminophenol, and the like; narcotizing medicaments, for example, morphine, dihydromorphinone, scopolamine, ccleine, and the like.

The experimental and test data on bases of varying Thus, the following medicinal ingredients and appropriate compositions are summarized in Tables I and II.

TABLE I Bases for extrusion molding [Figures are percent by weight] Tween 2 Polyethylene sorbitol bee wax derivative Corn starch- Cane sugar- Propylene giy Zinc oxide- Glycerol lnon. Tegacld regular Behavior in water 5isperses in Good solu- Good solu- Good solu- Dis persesin Poor dis- Fa s 01th Tahiti water. bility. bility. bility. water. pcrsibility. bllity. bility. Extrusion results Very sticky. T00 sticky-. T00 sticky-. Too sticky.. Too stlcky Fair Dsuolora- Too soft.

l A glyceryl monostearate-ilethylaminoethyl alkyl amide phosphate emulsifier.

TABLE II Bases for extrusion molding [Figures are percent by weight] I J K L M N O P Titanium dioxide Polyethylene sorbitol beeswax derivative.-.

Glycerol mnnostcaraie...

Corn starch Cane sugar Tween 20..

Propylene g Behaviorinwater Fair-.. Fair-.. ,l Bust m whole series.

Extrusion results.. Fair... Fair... Sticky. DiscolorccL. Fair... Stick Fair... Best-101M110 \v n 0 series.

gamma-picolinium chloride, sulfadiazine, phenol, second- The data in Tables I and II show that the ingredients are critical to the compositions suitability for extrusion and water-dispersibility. Until the successful composition was formulated, there were repeated failures in either extrusion or water-dispersibility, and in some cases in both of these necessary characteristics. It can be ob served that many formulations were too soft, stuck in the extrusion apparatus or discolored. Others failed to meet the requirements of completely dispersing in deionized water within two hours at body temperature.

The following examples are to set forth the best mode contemplated by the applicants of carrying out the sub: ject invention but are not to be construed as limiting.

EXAMPLE 1.UNMEDICATED BASE A satisfactory base is prepared from the following types and amounts of ingredients, the. parts being: given by'weight:

Formula. HO(CeHrO)ACsHaOhtCzHrO)cH wherein b e 1)ualcs8275 6:0 32 and a+c equals 136 to 138, molecular weight a on The PEG. 4000, polyoxyethylene sorbitan tristearate, spermaceti, and the ethylenev oxide-polypropylene glycol condensation product are melted together at l80.to 190 degrees Fahrenheit. The coloring powder, starch and about fifteen percent of the beta lactose. are dispersed in the P.E.G. 600. The dispersion is added to the melted mixture. The balance of the beta lactose is added. The whole is stirred and the temperature maintained at 180 to 190 degrees Fahrenheit to ensure smoothness. The completed base is allowed to cool under refrigeration. Such a base is storage-stable, water-dispersible and suitable for extrusion-molding. Preparationsshaped from this base by extrusion are unaffected by' a temperature as high as 47 degrees centigrade, maintaining their'form and rigidity for at least one month at this excessive temperature.

EXAMPLE 2.UNMEDICATED BASE- Following the procedure of Example 1, a satisfactory base is prepared from the following types and amounts of ingredients, the parts being again given by weight:

Parts PEG. 4000 965 Polyoxyethylene sorbitan tristearate 300 Spermaceti 330 P.E.G. 200 360 Polyoxyethylene stearate' 150 Sucrose 725 Coloring powder 15 Starch, bolted 100 Purified wood cellulose 20 Preparations shaped from this base by extrusion are unaffected by a temperature as high as 47 degrees centigrade, maintaining their form and rigidity for at least one month at this excessive temperature.

EXAMPLE 3.MEDICATED PREPARATION A satisfactory medicated preparation is shaped from thefollowing types and amounts of materials by extrusion-molding; the parts being expressed by weight:

The P.E.G. 6000, polyoxyethylene sorbitan monostearate and spermaceti are melted together at 180 to 190 degrees Fahrenheit. The coloring powder, starch, about fifteen percent of the sodium sulfate and the four medicinal agents are dispersed in the P.E.G. 400. The dispersion is added to the melted mixture. The balance of the sodium sulfate is added. The whole is stirred at I having a molecular weight of from about 200 to about 600; a member selected from the group consisting of solid polyoxyethylene sorbitan monostearate and poly- 1:80 to 19,0 degreesFahrenheit to ensure smoothness? 0 completed mass is allowed to cool sufliciently,: then poured into chilled containers which are stored, approximately 24 hours under refrigerationprior to extrusion to form shaped preparations weighing three gramseach. This preparation is eificacious in the treatment of rectal conditions involving inflammation and/or infection.

EXAMPLE 4.MEDICATED SUPPOSITORSE Following the procedure of Example 3, 25,000"medi= cated suppositories are prepared from the following types and amounts of materials:

P.E.G. 6000 53 lbs. 4oz. 7 Polyoxyethylene sorbitan monostearate 16 lbs. 802; Spermaceti 18 lbs. 4 oz. P.E.G. 400 19 lbs. 12102. Ethylene oxide-polypropylene glycol condensation product 8 lbs. 4" oz. Beta lactose 40 lbs. Coloring powder 13 oz. 'grs. Starch, bolted 6 lbs 10 oz. 1 Hydrocortisone acetate 13-oz.-l00 grs Neomycin sulfate 13 oz. 100 grs.

These suppositories are unafiected by a temperature as high as 47 degrees centigrade, maintaining their 'form and rigidity for at least one month. Nevertheless, they disperse completely in water within two hours at body temperature.

EXAMPLE 5.MEDICATED surrosr'ronr Following the procedure of Example 3, medicated suppositories are prepared from the following types and amounts of materials, the parts'being given by weight:

' Pans P.E.G. 4000 750 Polyoxyethylene sorbitan monostearate 300 Sperrnaceti 330 P.E.G. 400 320 Ethylene oxide-polypropylene glycol condensation a product Beta lactose i640 Coloring powder T 15 Starch, bolted 1'20 Aminophylline 375 in the art, and the invention is therefore to be limited only by the scope of the appended claims.

What is claimed is:

l. A pharmaceuticalpreparation suitable for'shaping by extrusion-molding and comprising a polyethylene glycol of the formula H(OCH CH ),,OH having a mo lecular weight of from about 4000 to about 6000; a liquid polyethylene glycol of the formula H(OCH CH ),,OH

oxyethylene sorbitan tristearate; spermaceti; a member selected from the group consisting of an ethylene oxide-. polypropylene glycol condensation product of the formula HO (C H O) (C H O) (C H O H With a polypropylenebase molecular weight of about 1750 and a total molecular weight of about 8750, polyoxyethylene palmitate and a solid polyoxyethylene stearate having a hydrophile lypophile-balance value of from about 16 to about 18; and a non-toxic, substantially dry adjuvant mixture of which between about eighty and about ninety percent by weight is water-soluble.

2. The composition of claim 1 which contains in addition a medicament.

3. A pharmaceutical preparation suitable for shaping by extrusion-molding and comprising from about 23 to about 35 percent by weight of a polyethylene glycol of the formula H(OCH CH ,OH having a molecular weight of from about 4000 to about 6000; from about ten to about thirteen percent by weight of a liquid polyethylene glycol of the formula H(OCH CH ),,OH having a molecular weight of from about 200 to about 600; from about nine to about eleven percent by weight of a member selected from the group consisting of solid polyoxyethylene sorbitan monostearate and polyoxyethylenesorbitan tristearate; from about ten to about twelve percent by weight of spermaceti; from about four to about six percent by weight of a member selected from the group consisting of an ethylene oxide-polypropylene glycol condensation product of the formula HO(C H O)(C H O)(C H O)H with a polypropylenebase molecular weight of about 1750 and a total molecular weight of about 8750, polyoxyethylene palmitate and a solid polyoxyethylene stearate having a hydrophilelypophile-balance value of from about 16 to about 18; and from about 26 to about 40 percent by weight of a non-toxic, substantially dry adjuvant mixture of which between about eighty and about ninety percent by weight is water-soluble.

4. A pharmaceutical preparation shaped by extrusionmolding comprising from about 23 to about 35 percent -by weight of a polyethylene glycol of the formula H(CH CH ),,OH having a molecular weight of from about 4000 to about 6000; from about ten to about thirteen percent by weight of a liquid polyethylene glycol of the formula H(OCH CH ),,OH having a molecular weight of from about 200 to about 600; from about nine to about eleven percent by weight of a member selected from the group consisting of solid polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan tristearate; from about ten to about twelve percent by weight of spermaceti; from about four to about six percent by weight of a member selected from the group consisting of an ethylene oxide-polypropylene glycol condensation product of the formula with a polypropylene-base molecular weight of about 1750 and a total molecular weight of about 8750, polyoxyethylene palmitate and a solid polyoxyethylene stearate having a hydrophile-lypophile-balance value of from about 16 to about 18; from about 26 to about 40 percent by weight of a non-toxic, substantially dry adjuvant mixture of which between about eighty and about ninety percent by weight is water-soluble and a medicament.

5. A pharmaceutical preparation shaped by extrusionmolding comprising from about 23 to about 35 percent by weight of a polyethylene glycol of the formula H(OCH CH ),,OH having a molecular weight of from about 4000 to about 6000; from about ten to about thirteen percent by weight of a liquid polyethylene glycol of the formula H(OCH CH ),,OH having a molecular weight of from about 200 to about 600; from about nine to about eleven percent by weight of a member selected from the group consisting of solid polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan tristearate; from about ten to about twelve percent by weight of spermaceti; from about four to about six percent by weight of a member selected from the group consisting of an ethylene oxide-polypropylene glycol condensation product of the formula HO(C H O) (C l-l O) (C H O)H with a polypropylene-base molecular weight of about 1750 and a total molecular weight of about 8750, polyoxyethylene palmitate and a solid polyoxyethylene stearate having a hydrophile-lypophile-balance value of from about 16 to about 18; from about 26 to about percent by weight of a non-toxic, substantially dry adjuvant mixture of which between about eighty and about ninety percent by weight is water-soluble and from about 0.5 to about twelve percent by weight of a medicament.

6. A suppository shaped by extrusion-molding comprising about 32 percent by weight of a solid polyethylene glycol of the formula H(0CH CH ),,OH having a molecular weight of about 6000; about twelve percent by weight of a liquid polyethylene glycol of the formula H(0CH CH ),,OH having a molecular weight of about 400 about ten percent by weight of solid polyoxyethylene sorbitan monostearate; about eleven percent by weight of spermaceti; about five percent by weight of an ethylene oxide-polypropylene glycol condensation product of the formula HO(C H O)(C H O)(C H,O)H with a polypropylene-base molecular weight of about 1750 and a total molecular weight of about 8750; about 25 percent by weight of beta lactose; about four percent by weight of starch; about 0.5 percent by weight of titanium dioxide; about 0.5 percent by weight of hydrocortisone acetate; and about 0.6 percent by weight of ncomycin sulfate.

References Cited in the tile of this patent UNITED STATES PATENTS 2,394,616 Knoth et al Feb. 12, 1946 2,538,127 Saunders Jan. 16, 1951 2,677,700 Jackson May 4, 1954 2,854,378 Buckwalter Sept. 30, 1958 FOREIGN PATENTS 784,659 Great Britain Oct. 16, 1957 OTHER REFERENCES Dolder: Schweizerische Apotheker-Zeitung, vol. 89, No. 22, June 2, 1951, pp. 381-382.

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1. A PHARMACEUTICAL PREPARATION SUITABLE FOR SHAPING BY EXTRUSION-MOLDING AND COMPRISING A POLYETHYLENE GLYCOL OF THE FORMULA H(OCH2CH2)NOH HAVING A MOLECULAR WEIGHT OF FROM ABOUT 4000 TO ABOUT 6000; A LIQUID POLYETHYLENE GLYCOL OF THE FORMULA H(OCH2CH2)NOH HAVING A MOLECULAR WEIGHT OF FROM ABOUT 200 TO ABOUT 600; A MEMBER SELECTED FROM THE GROUP CONSISTING OF SOLID POLYOXYETHYLENE SORBITAN MONOSTEARATE AND POLYOXYETHYLENE SORBITAN TRISTERATE; SPERMACETI; A MEMBER SELECTED FROM THE GROUP CONSISTING OF AN ETHYLENE OXIDEPOLYPROPYLENE GLYCOL CONDENSATION PRODUCT OF THE FORMULA HO(C2H4O) (C3H6O) (C2H4O)H WITH A POLYPROPYLENEBASE MOLECULAR WEIGHT OF ABOUT 1750 AND A TOTAL MOLECULAR WEIGHT OF ABOUT 8750, POLYOXYETHYLENE PALMITATE AND A SOLID POLYOXYETHYLENE STEARATE HAVING A HYDROPHILELYPOPHILE-BALANCE VALUE OF FROM ABOUT 16 TO 18, AND A NON-TOXIC, SUBSTANTIALLY DRY ADJUVANT MIXTURE OF WHICH BETWEEN ABOUT EIGHTY AND ABOUT NINETY PERCENT BY WEIGHT IS WATER-SOLUBLE. 